Gastric reflux, gastritis, dyspepsia, stomach ulcers, duodenal ulcers and other gastric acid disturbances affect more than one in 600 people. About 10% of the world's population have gastric or duodenal ulcers at some time in their lives. Disturbances such as gastritis, dyspepsia, 70% of stomach ulcers and 90% of duodenal ulcers are thought to be caused by the bacterium Helicobacter pylori. In other cases the causative agent of the ulcers is thought to be nonsteroid anti-inflammatory drugs (NSAIDs) or conditions leading to hypersecretion of gastric acid. Gastric reflux occurs when the muscular valve at the lower end of the oesophagus (i.e. the lower intraoesophageal sphincter) malfunctions, by transient relaxation, allowing acid from the stomach into the oesophagus. Chronic gastric reflux leads to high level exposure of the oesophagus to acid, and leads to complications known as gastrooesophageal reflux disease (GORD).
The treatment in gastric acid secretion disturbances involves reduction of gastric acid production and/or secretion. In gastric reflux a reduction in acid levels allows the healing of the oesophageal mucosa and then prophylaxis involves maintenance therapy to keep acid levels low and to thereby prevent recurrence. In the case of ulcers a reduction in acid levels allows the healing of the stomach or duodenal mucosa, and then prophylaxis involves maintenance therapy to keep acid levels low to thereby prevent damage recurring. If the causative agent of the ulcer is the bacterium Helicobacter pylori, the treatment involves a reduction of acid levels, which allows acid sensitive broad-spectrum antibiotics to be used to eradicate the bacterium and to cure the disease.
It is understood that gastric acid secretion is regulated by neuronal (acetylcholine), hormonal (gastrin) and paracrine (histamine:somatostatin) mechanisms. All the pathways converge on and modulate the activity of the gastric proton pump enzyme, H+,K(+)-ATPase of the parietal cell. Precise information on the mechanisms of pump activation and identification of specific receptor subtypes in this process has led to the development of drugs capable of inhibiting and modulating acid secretion for treatment and/or prophylaxis. These include competitive antagonists that interfere with acid stimulatory receptors (such as muscarinic M1-receptor antagonists and histamine H2-receptor antagonists e.g. famotidine, cimetidine, and ranitidine) as well as more potent non-competitive inhibitors of the gastric proton pump H+,K(+)-ATPase (e.g. omeprazole, pantoprazole, lansoprazole, and rabeprazole). It also includes prostaglandin E receptor agonists such as misoprastol. Where the causative agent of the ulcer or acid disturbance is the bacterium Helicobacter pylori, the introduction of anti-Helicobacter therapy using antibiotics in admixture with these gastric acid reducing agents has increased the number of options available for the treatment and management of the disease.
There are however, a number of problems with and limitations in using the above-identified antagonists (inhibitors) and agonists in treatment and maintenance therapy. For instance, agonists such as misoprastol and antagonists such as histamine H2 receptor antagonists, are often the first line drugs used in therapy and maintenance. However, such agents are not completely effective because they modulate or interfere with only one of the pathways leading to acid secretion. They are slow in the treatment of the disease and it has been found that the relapse rates in maintenance therapy are high.
Further, because the effectiveness of such agents in some treatments is for a short time they are often taken a number of times per day and thus there is usually a lower compliance rate compared with drugs taken once a day or less often. Furthermore, because these agents cause adverse side-effects, lower doses, which are less effective, are commonly used. Finally, it has been found that these agents interact with cytochrome P450. Thus these agents cannot be taken in conjunction with other drugs such as diazepam, pyrethrin, and/or warfarin in multiple therapies.
Proton pump antagonists, the second line drugs, have become the more preferred agents in treatment and maintenance therapy because they are more effective than misoprastol and histamine H2 receptor antagonists. Proton pump antagonists are generally thought to be effective when taken once a day although recently it has been estimated that up to 40% of gastric reflux patients take them twice a day. Surprisingly, standard dosage, whether it is taken once or twice a day, does not reduce and maintain acid levels at the required therapeutic level throughout an entire day. Recent reports suggest that 15% and speculated up to 40% of gastric reflux patients that take standard doses twice a day still do not have sufficient effect at night. This can cause discomfort, a relapse of gastric reflux and other disturbances. Moreover, when higher doses or multiple standard doses are necessary for the desired effect to be achieved, they may cause inacidity in the stomach over extended periods of time. This inacidity has been found to cause hypergastrinaemia which can lead to G-cell abnormalities, ECL hyperplasia or other abnormalities in humans. Long term use of proton pump antagonists has also been linked with colon cancer. Surprisingly, it has recently being found that some conditions are refractory to treatment with the current proton pump inhibitor drugs. This includes 6-8% of chronic ulcer sufferers and 5-15% of gastric reflux sufferers. Furthermore, like misoprastol and histamine H2 receptor antagonists, proton pump antagonists cannot be taken in conjunction with other drugs such as diazepam, pyrethrin, and/or warfarin in multiple therapies, because these agents interact with cytochrome P450.
The proton pump antagonists are also involved in Helicobacter pylori eradication therapy where complicated drug regimens are commonly employed. For instance, in some regimens the antagonists are taken twice a day together with multiple daily doses of two different antibiotics for one to two weeks. In other regimens the antagonists are taken for a further two weeks making a total of one month. Because of the complicated drug regimens and the adverse side effects, patient compliance has often been found to be a problem. Non-compliance results in ineffective eradication therapy where because the antagonists are not been taken in the correct dosage the gastric acid in the stomach is not reduced either sufficiently or quickly enough and for a long enough time to enable acid sensitive antibiotics to work. In fact various reports suggest that conservatively about 15% or more of patients undergoing Helicobacter pylori eradication therapy are not cured for this very reason.
It is therefore an object of the present invention to provide acid reducing products and processes for using such products where one or more of the above problems and limitations are ameliorated.